CXCL9-Dependent Immune Networks of Spontaneous Tertiary Lymphoid Structures in a Murine Subcutaneous Tumor Model

Recent research has unveiled the role of CXCL9 in the formation and function of spontaneous tertiary lymphoid structures (TLS) in a subcutaneous tumor model of mice. TLS are clusters of immune and stromal cells, which can contribute to tumor clearance and improve outcomes in immune checkpoint blockade (ICB) therapy. In this study, a subcutaneous tumor model with natural TLS formation was developed by manipulating tumor antigen expression.

These TLS consisted of B and T cells near high endothelial venules within the peritumoral adipose tissue. The organization of TLS was driven by the expression of chemokines, with CCL21 in the T cell zone and CXCL13 in the B cell region. Genome-wide analysis revealed that the immune composition in TLS formed in peritumoral tissue was similar to human cancer TLS.

Following anti-PD-L1 ICB treatment, TLS expanded, accompanied by increased interferon responses in macrophages and tumor clearance. CXCL9, an interferon-inducible chemokine, emerged as a crucial regulator of the TLS microenvironment. CXCL9-producing macrophages were found within TLS and interacted with B cells post-ICB treatment.

When CXCL9 was deficient, B cell recruitment to the peritumoral tissue and TLS formation were reduced. Additionally, CXCL9 was shown to promote antigen-specific responses in T and B cells within the tumor and TLS niche. The study establishes a mouse model that naturally forms TLS and elucidates the cellular and molecular networks that govern their formation and function.

This model offers an opportunity to investigate how TLS develop and to test therapeutic strategies aimed at stimulating TLS formation to improve cancer therapy.